PROJECT SUMMARY/ABSTRACT As Zika virus sweeps through Latin America, it is leaving behind an epidemic of children devastated by micro- cephaly and other adverse neurologic outcomes. Before we can develop new diagnostic and therapeutic strat- egies to prevent these devastating outcomes, we must understand factors that drive Zika virus pathogenesis. In this proposal, we seek to investigate the role of innate natural killer (NK) cells in Zika virus infection. NK cells are `early responders' to viral infections and set the stage for subsequent adaptive responses?playing a criti- cal role in the balance between protection and immunopathogenesis during viral infection. Our prior studies demonstrate that the human NK cell repertoire is astoundingly diverse and is associated with the risk of viral acquisition. To date, no studies have evaluated the role of NK cells in Zika virus infection; however, NK cells rapidly expand and become activated during the response to flaviruses including dengue virus and West Nile virus. Our overall goal is to understand how NK cells contribute to the balance between protection and im- munopathogenesis during Zika virus infection. We hypothesize that specific subsets of human NK cells re- spond to ZIKV, contributing to distinct functional outcomes that can shift the balance between protection and immunopathogenesis. We therefore aim to define the NK cell subsets responding to Zika virus, the receptors involved, and their functional profile both in vivo and in vitro. This proposal will identify the mechanisms by which NK cells recognize and respond to ZIKV, providing critical insight into the role of NK cells in immuno- pathogenesis vs. protection from ZIKV. 1